2-(5&#39;-phenyl-m-terphenyl - 4 - yloxy) lower aliphatic monocarbocyclic acids and esters thereof

ABSTRACT

THE INVENTION RELATES TO 2 - (5&#39;&#39;-PHENYL-M-TERPHENYL-4YLOXY) LOWER ALIPHATIC MONOCARBOCYLIC ACIDS AND THE CORRESPONDING LOWER ALKYL ESTERS, AND TO A PROCESS FOR THEIR PRODUCTION. THE COMPOUNDS ARE USEFUL AS HYPOLIPIDEMICS, THIS INVENTION RELATES TO DERIVATIVES OF ALIPHATIC ACIDS.

United States Patent Oflice Patented Aug. 10, 1971 ABSTRACT OF THEDISCLOSURE The invention relates to 2 (5'-phenyl-m-terphenyl-4- yloxy)lower aliphatic monocarbocylic acids and the corresponding lower alkylesters, and to a process for their production. The compounds are usefulas hypolipidemics.

This invention relates to derivatives of aliphatic acids.

In particular the invention pertains to 2-(5-phenyl-mterphenyl-4-yloxy)lower aliphatic monocarbocylic acids and the corresponding lower alkylesters. The invention also relates to intermediates useful in preparingsaid acids and esters as well as processes for preparing saidintermediates and said acids and esters.

The substituted aliphatic acids and esters of the present invention maybe represented structurally as follows:

wherein each of R and R independently represents hydrogen or straightIII wherein R R and R are as defined, X represents halogen having anatomic weight of from 35 to 127, i.e., chloro, bromo and iodo, and Mrepresents an alkalimetal preferably sodium or potassium.

The above process is conveniently carried out in an inert organicsolvent and at elevated temperatures. Preferably the reaction is carriedout at a temperature of from about 20 C. to about C. and in the samesolvent employed for the preparation of the alkali-metal salt derivativeof Formula II from the corresponding phenol discussed in further detailhereinafter. The resulting product (I) is readily recovered inconventional manner.

It will be readily appreciated by one skilled in the art that thecompounds of Formula I wherein R is hydrogen, i.e., the free acids, mayalso be obtained from the corresponding esters of Formula I (i.e., whereR is alkyl) by simple basic hydrolysis of the ester in conventionalmanner. The hydrolysis is conveniently carried out by treating the esterwith an alcoholic solution of an alkali-metal hydroxide, e.g., potassiumhydroxide in methanol.

Various of the 2-halo substituted alkanoic acids and esters of FormulaHI employed in the above-illustrated process are known and can beprepared by methods described in the literature. Such others .which maynot be specifically described in the literature can be prepared fromavailable material in analogous manner.

The alkali-metal salts of 4- (m-terphenyl 5 yl) phenol (Formula II) areconveniently prepared by reacting the corresponding phenol with analkali-metal hydride, e.g., sodium hydride or potassium hydride, at roomtemperature (2025 C.) in an inert substantially anhydrous organicsolvent. Suitable solvents include dimethylacetamide, diethylacetamideand dimethylformamide. As previously indicated hereinabove the solventemployed in preparing the phenolate is preferably employed in carryingout the subsequent reaction of the phenolate (II) with the appropriate2-halo substituted alkanoic acid or ester (III). The preparation of thephenol, i.e., 4-(mterphenyl-S-yDphenol is illustrated in Example 1hereinafter.

The compounds of Formula I are useful because they possesspharmacological activity in animals. In particular, the compounds areuseful as hypolipidemic agents having hypocholesteremic and/orhypotriglyceridemic activity, as indicated by tests on a group of whiterats which are given 1050 mg. per kg. of body weight per diem of thecompound orally, for six days, followed by extraction with isopropanolof serum or plasma after anesthetizing the rats with sodiumhexobarbital, and then noting the cholesterol and triglyceride contentsas compared to those of a control group. The cholesterol andtriglyceride contents are determined by the methods described byLofland, H.B., Anal. Biochem. 9:393 (1964): (Technicon method N 24a):and Kessler, G., and Lederer, H. Technicon Symposium, Mediad Inc., NewYork, pages 345-347 (1965), respectively. For such usage, the compoundsmay be administered orally as such as admixed with conventionalpharmaceutical carriers. The dosage administered may vary depending onthe particular compound employed, the therapy desired and the severityof the condition being treated. In general, satisfactory results areobtained when administered at a daily dosage of from about 4 milligramsto about 30 milligrams per kilogram of animal body weight, preferablygiven in divided doses, 2 to 4 times a day, or in sustained releaseform. For most mammals the total daily dosage is from about 0.05 gram toabout .4 gram of the compound, and the dosage forms suitable forinternal use comprise from about 12.5 milligrams to about 200 milligramsof active compound in intimate admixture with a solid or liquidpharmaceutically acceptable carrier or diluent.

For above usages, oral administration with carriers may take place insuch conventional forms as tablets, dispersible powders, granules,capsules, syrups and elixirs. Such compositions may be preparedaccording to any method known in the art for the manufacture ofpharmaceutical compositions, and such compositions may contain one ormore conventional adjuvants, such as sweetening agents, flavoringagents, coloring agents, and preserving agents, in order to provide anelegant and palatable preparation. Tablets may contain the activeingredient in admixture with conventional pharmaceutical excipients,e.g., inert diluents such as calcium carbonate, sodium carbonate,lactose and talc, granulating and disintegrating agents, e.g., starchand alginic acid, binding agents, e.g., starch, gelatin and acacia, andlubricating agents, e.g., magnesium stearate, stearate acid and talc.The tablets may be uncoated or coated by known techniques to delaydisintegration and adsorption in the gastro-intestinal tract and therebyprovide a sustained action over a longer period. Similarly, suspensions,syrups and elixirs may contain the active ingredient in admixture withany of the conventional excipients utilized for the preparation of suchcomposition, e.g., suspending agents (methylcellulose, tragacanth andsodium alginate), wetting agents (lecithin, polyoxyethylene stearate andpolyoxyethylene sorbitan monooleate) and preservatives(ethyl-phydroxybenzoate). Capsules may contain the active ingredientalone or admixed with an inert solid diluent, e.g., calcium carbonate,calcium phosphate and kaolin. The preferred pharmaceutical compositionsfrom the standpoint of preparation and ease of administration are solidcompositions, particularly hardfilled capsules and tablets.

The compounds of Formula I wherein R is hydrogen (i.e. free acids) maybe similarly administered in the form of their non-toxicpharmaceutically acceptable salts. Such salts do not materially differfrom the free acid forms in their pharmacological effect and areincluded within the scope of the invention. As illustrative of suchsalts there may be included aluminum salt; non-toxic alkali metal salts,e.g., potassium and sodium salts; non-toxic alkaline earth metal salts,e.g., magnesium and calcium salts; salts with N-containing bases such asammonium salts and pharmaceutically acceptable primary, secondary andtertiary amine salts, e.g., ethanol amine salts, diethanol amine salts,and the like. Such salts are prepared in conventional manner.

A representative formulation is a tablet prepared by conventionaltabletting techniques and containing the following ingredients:

Ingredients: Weight (mg) 2-methyl-2-(5-phenyl m terphenyl-4-yloxy)propionic acid .50 Tragacanth l Lactose 197.5 Corn starch 25 Talcum l5Magnesium stearate 2.5

The following examples show representative compounds encompassed withinthe scope of this invention and the manner in which such compounds areprepared. However, it is to be understood that the examples are forpurposes of illustration only and are not intended as in any waylimiting the scope of the invention which is defined in the appendedclaims.

EXAMPLE 1 12-meth yl-2- 5 -phenyl-m-terphenyl-4-yloxy pro pionic acidethyl ester Step A: Preparation of 4-(p-methoxyphenyl)-2-oxo-6-phenyl-3-cyclohexene-l-carboxylic acid ethyl ester.To a solution of 93g. of 4'-methoxychalcone (a known compound) prepared by reaction ofp-methoxyacetophenone and benzaldehyde dissolved in 6.5 liters absoluteethanol containing 54 g. anhydrous potassium carbonate is added 63.5 g.ethyl acetoacetate. The resulting mixture is stirred at room temperature(20 C.) for 22 hours, evaporated in vacuo to a thick slurry which istreated with 500 ml. methylene chloride. The resulting solution isfiltered and the filtrate evaporated in vacuo to obtain a viscous oilwhich is taken up in 350 ml. 95% ethanol. The crude product iscrystallized from the ethanol and recrystallization from ethanol gives4-(p-methoxyphenyl)-2-oxo-6- phenyl-3-cyclohexene-l-carboxylic acidethyl ester, M.P. 1055-107 C.

Step B: Preparation of 3-(p-methoxyphenyl)-5-phenyl-2-cyclohexen-l-one.-To a solution of 43 g. of4'(p-methoxyphenyl)-2-oxo-6-phenyl 3 cyclohexene 1 carboxylic acid ethylester dissolved in 860 ml. acetic acid is added 430 ml. hydrochloricacid. The resulting mixture is refluxed overnight, evaporated in vacuoto obtain a crude oil which is dissolved in 500 ml. methylene chloride.The resulting solution is washed first with 200 ml. water, then 200 ml.saturated sodium bicarbonate solution, and again with 200 ml. water. Theorganic phase is dried over anhydrous magnesium sulfate, evaporated invacuo to remove solvent, and the resulting solid twice crystallized from350 ml. ethanol to obtain yellow needles of3-(pmethoxyphenyl)-5-phenyl-2-cyclohexen-1one, M.P. 103- 104" C.

Step C: Preparation of 3 (pmethoxyphenyl)-1,5-diphenyl-Z-cyclohexen-1-ol.A solution of 36.5 g. of3-(pmethoxyphenyl)-5-phenyl 2 cyclohexen-l-one prepared as in Step Bdissolved in 30 m1. dry tetrahydrofuran is slowly added dropwise withstirring to a solution of about 0.2 mole of freshly preparedphenylmagnesium bromide in ml. of tetrahydrofuran, while maintaining thecombined solutions during such addition at temperatures of about -S C.(Dry-Ice-acetone bath). Thirty minutes after addition the resultingreaction mixture is allowed to warm to room temperature (20 C.) over aperiod of one hour. The reaction mixture is then quenched with 250 ml.of saturated ammonium chloride solution, and the resulting aqueousalkaline (pH 8-9) emulsion extracted three times each with 200ml.diethyl ether. The combined ethereal extracts are first washed with 50ml. saturated sodium chloride solution, and then extracted twice eachwith 200 ml. of a 10% solution of tartaric acid. The combined acidicextracts are pack-washed twice each with 100 ml. of ether and then madebasic (ph 10) with 50% sodium hydroxide. The resulting emulsion isextracted three times each with 200 ml. ether. The combined etherealextracts are Washed with 50 ml. saturated sodium chloride solution,dried over anhydrous magnesium sulfate and finally concentrated in vacuoto give a clear, bright yellow viscous oil of3-(p-methoxypheny1)-1,5-diphenyl-2-cyclohexen-l-ol.

Step D: Preparation of '-(p-methoxyphenyl) m terphenyl A solution of 480g. of 3-(p-methoxyphenyl)-1,5-diphenyl-2-cycl0hexen-1-0l in 2500 ml.methylene chloride is cooled to minus 50 C. and there is added thereto195 ml. thionyl chloride in 400 m1. methylene chloride. The resultingmixture is maintained at minus 50 C. for '1 hour, allowed to warm to 0C., and then is poured onto mixture of 2 kilograms crushed ice and aconcentrated solution of mols sodium hydroxide. The organic phase isseparated and evaporated in vacuo to obtain a. thick slurry Which isfiltered. The recovered solid is recrystallized from isopropanol toobtain 5'-(p-methoxyphenyl)- m-terphenyl, M.P. 132-136 C.

Step E: Preparation of 5'-phenyl-m-terphenyl-4-ol.-A solution of 230 g.of 5-(p-methoxyphenyl)-m-terphenyl obtained from Example 19 in 1000 ml.xylene is heated to 125 C. and there is added thereto 160 g. aluminumchloride. The resulting mixture is refluxed for 5 hours, cooled to 100C., and poured onto 2 kilograms of crushed ice. The organic phase isallowed to separate, is dried over magnesium sulfate, heated with oneliter of petroleum ether and cooled to 0 C. overnight. The resultingprecipitate is filtered and the crude product is crystallized from 500ml. cyclohexane and the solids recovered by filtration after allowing tostand 2.5 days at 5 C. This material is then recrystallized from a 1:1mixture of cyclohexane and benzene using 50 g. of charcoal to removeimpurities, to obtain 5'-phenyl m terphenyl-4-ol, M.P. 127-130 C. andalso is referred to as terphenylphenol.

Step F: Preparation of2-methyl-2-(5-phenyl-m-terphenyl-4-yloxy)propionic acid ethyl ester.4.8g. of sodium hydride, (50%) is suspended in 200 ml. of drydimethylacetamide (DMA), 32.2 g. of terphenylphenol are addedportionwise and the mixture stirred at room temperature until all thesodium hydride has reacted. To the resulting sodium salt of theabove-mentioned phenol 20 g. of ethyl bromoisobutyrate are added and themixture heated to 100 C. on a water bath for 24 hours. The solvent isthen evaporated in a vacuum, the residue taken up in ether andsubsequently extracted consecutively with 200 m1. of water, 200 ml. of 1N hydrochloric acid, 200 ml. of water and 200ml. of a saturated sodiumbicarbonate solution. After drying over magnesium sulfate, the ether isevapo rated to yield 2-methyl-2-(5'ephenyl-m-terphenyl-4-yloxy)propionic acid ethyl ester.

EXAMPLE 2 2-methyl-2-(5-phenyl-m-terphenyl-4-yloxy) propionic acid 9 g.of 2-methyl-2-(5'-phenyl m terphenyl-4-yloxy) propionic acid ethyl esterare dissolved in a solution of 2.0 g. of potassium hydroxide in 40 ml.methanol and left at room temperature for 3 days. The solvent is thenevaporated in vacuo, the residue dissolved in water, extracted twicewith 50 ml. ether and acidified with 20 ml. 2 N hydrochloric acid. Theproduct is extracted with 3x 50 ml. of diethylether, the organic phasewashed with 50 ml. of a saturated sodium chloride solution and thendried over magnesium sulfate. The organic phase is then evaporated offto obtain 2-methyl-2-(5'-phenyl-m-terphenyl-4-yloxy) propionic acid.

What is claimed is:

1. A compound of formula wherein each of R and R independentlyrepresents hydrogen or straight chain lower alkyl and R representshydrogen or straight or branched chain lower alkyl or, when R representshydrogen, the pharmaceutically acceptable salts thereof.

2. A compound of claim 1 which is 2-methyl-2-(5'-phenyl-m-terphenyl-4-yloxy)propionic acid or a pharmaceuticallyacceptable salt thereof.

3. A compound of claim 1 which is 2-methyl-2-(5-phenyl-m-terphenyl-4-y1oxy)propionic acid ethyl ester.

References Cited Bencze, W. L., et al., J. Med. Pharm. Chem., 10(2),138-144 (1967).

JAMES A. PA'ITEN, Primary Examiner J. F. TERAPANE, Assistant ExaminerUS. 01. X.R.

